Clusterin is a widely distributed glycoprotein with a diverse set of biologic actions. A unique and defining feature of clusterin is its induction in many organs at times of tissue injury and remodeling. In the kidney, increased expression is observed during ontogeny, in developmental disorders such as renal cystic diseases, and in a variety of acute and chronic renal injury states. The roles subserved by clusterin are unclear. We hypothesize clusterin functions to initiate or maintain cell interactions, a common requirement of the states in which it is induced. The specific aims of this grant are to define the effects of clusterin on renal cell interactions. We will test whether overexpression of clusterin enhances, or blocking clusterin expression by gene deletion inhibits renal epithelial cell aggregation and adhesion. The ability of clusterin to function as an epithelial cell morphogen will also be tested in three dimensional cultures of renal epithelial cells. Based on the developmental regulation of clusterin during renal ontogenesis we will study its expression and function in the metanephric organ culture model of renal development. The long-term objective of this grant is to gain insight into what appears to be a novel mechanism of cell adhesion and aggregation. We hope to further our understanding of the complex cell interactions which occur during renal development and in states of tissue injury and remodeling including acute and chronic renal disease. The often immediate and fulminant expression of clusterin in disease states is at present puzzling, both from the standpoint of the specific molecular species and cellular pathways ultimately eliciting such expression, as well as the roles subserved by clusterin once induced. The studies proposed in this grant may begin to unravel this puzzle and provide a potential therapeutic strategy to modify the cellular response to injury.